Serotonin transporter (5‐HTT) gene and bipolar affective disorder

Esterling, Lisa E.; Yoshikawa, Takeo; Turner, Gordon; Badner, Judy A.; Bengel, Dietmar; Gershon, Elliot S.; Berrettini, Wade H.; Detera‐Wadleigh, Sevilla D.

doi:10.1002/(sici)1096-8628(19980207)81:1<37::aid-ajmg7>3.3.co;2-b

Cited by 30 publications

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“…48,59 The 31 papers finally selected reported 43 studies related to the review objective in total since each paper frequently reported several separate studies. In total, 17 population-based studies 9,14,33,34,38,46,50,51,56,60,61,66,[68][69][70] and six family-based studies 12,32,42,53,63,74 were about 5-HTTLPR. A total of 16 population-based studies 27,33,35,38,41,47,[49][50][51]54,56,58,60,61,70,75 and four family-based studies 12,52,57,63 were about the intron 2 VNTR.…”

Section: Resultsmentioning

confidence: 99%

Population-based and family-based studies on the serotonin transporter gene polymorphisms and bipolar disorder: a systematic review and meta-analysis

et al. 2005

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The serotonin transporter (5-HTT) is a candidate gene for bipolar disorder (BPD). It has been investigated for association with the illness in a series of studies, but overall results have been inconsistent and its role in the disorder remains controversial. Systematic reviews using metaanalytical techniques are a useful method for objectively and reproducibly assessing individual studies and generating combined results. We performed two meta-analyses of published studies-both population-based and family-based studies-investigating the association between BPD and the 5-HTT gene-linked polymorphic region (5-HTTLPR) and the intron 2 variable numbers of tandem repeats (VNTR) polymorphisms. The literature was searched using Medline and Embase to identify studies for inclusion. We statistically joined population-based and family-based studies into a single meta-analysis. For both polymorphisms, our review revealed significant pooled odds ratios (ORs): 1.12 (95% CI 1.03-1.21) for the 5-HTTLPR and 1.12 (95% CI 1.02-1.22) for the intron 2 VNTR. Meta-regression showed that neither the study type (population-based vs family-based; P ¼ 0.41 for the 5-HTTLPR and P ¼ 0.91 for the intron 2 VNTR) nor the sample ethnicity (Caucasian vs non-Caucasian; P ¼ 0.35 for the 5-HTTLPR and P ¼ 0.66 for the intron 2 VNTR) significantly contributed to the heterogeneity of the meta-analyses. The observed ORs could be regarded simply as a very small but detectable effect of the 5-HTT, which has an additive effect when combined with other susceptibility loci. Alternative hypotheses on this finding were also discussed: a stronger effect of the haplotypes involving the two polymorphisms or other SNP markers; a more direct effect of these polymorphisms on specific phenotypes of BPD; and the presence of gene-environment interaction as a mediator of the genetic effects of 5-HTT. Keywords: bipolar disorder; serotonin transporter; polymorphisms; genetics; association study; meta-analysis Bipolar disorder (BPD), also known as manic-depressive illness, is a frequent and severe psychiatric disorder with the lifetime prevalence between 1 and 2% in the general population, being equally distributed across sexes. 1 The etiology is unknown although the presence of a complex dysfunction at multiple levels such as neurotransmitter system, prefrontallimbic-subcortical circuit and neuroendocrinological system has been suggested. 2 Family studies have indicated a marked increase in lifetime risk of the illness in first-degree relatives of the proband, varying between five and 10 times that of the general population. 3 Twin studies have shown an increased risk in monozygotic co-twins compared with dizygotic co-twins of a proband with BPD. The risk in monozygotic co-twins has been estimated at 45-75 times that of the general population. 3,4 Adoption studies have also shown that the risk of BPD is greater in biological relatives than in adoptive relatives of the probands. 5 Most of the segregation studies have shown that the inheritance of BPD cannot be explained b...

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Section: Resultsmentioning

confidence: 99%

Population-based and family-based studies on the serotonin transporter gene polymorphisms and bipolar disorder: a systematic review and meta-analysis

et al. 2005

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“…Association of allele 9 with unipolar depression was shown by Ogilvie and colleagues 18 but could not be replicated by Stoeber et al 19 Allele 12 has been shown to be associated with bipolar disorder by Collier et al 20 and this finding has been replicated by Rees et al 21 and Kunugi et al 22 A number of association studies have been reported, investigating the promoter polymorphism in affective 28 who studied association/linkage of the 5-HTT gene with bipolar affective disorder by the transmission disequilibrium test, all of the above mentioned studies used a casecontrol design for investigation of potential disease association with affective disorders or schizophrenia.…”

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Serotonin transporter gene and schizophrenia: evidence for association/linkage disequilibrium in families with affected siblings

et al. 2000

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The serotonergic (5-HT) system has been implicated in the etiopathogenesis of psychoses. Since the 5-HT transporter plays an important role in regulation of 5-HT transmission, its gene can be considered as a candidate for vulnerability to psychiatric disorders. Two polymorphic sites of the 5-HT transporter gene-5-HTTLPR, a VNTR in the 5Ј regulatory region, and a VNTR in the second intron-were studied in a sample of 61 families with schizophrenia for transmission disequilibrium. Each family contained at least two siblings affected with schizophrenia or schizoaffective disorder (mainly schizophrenic). One hundred and thirty-nine affected offspring with parental information for genotyping, were available for analysis. No preferential transmission of either short or long alleles of the promoter polymorphism was observed. However, a transmission distortion was detected for alleles of the intronic VNTR polymorphism ( 2 TDT max =14.33; P = 0.0002; corrected P value = 0.0003) resulting in more frequent than expected transmission of the 12 repeat allele. This finding adds additional evidence to the idea that the serotonergic system may be involved in development of psychoses. Molecular Psychiatry (2000) 5, 91-95. Disturbances in neurotransmission are considered to play a role in the development of psychiatric disorders. Several lines of evidence suggest that a master control neurotransmitter of complex neuronal communication may be serotonin (5-hydroxytryptamine, 5-HT), as reviewed by Lesch and Moessner. 1 While it is well established that the 5-HT system is involved in affective disorders, 1,2 its role in schizophrenia is currently being evaluated.It has been shown that the 5-HT receptor agonist mchlorophenylpiperazine (mCPP) can induce psychosis in schizophrenic patients, 3 while clozapine, the best known atypical antipsychotic drug, 4 displays an antagonist-activity at several 5-HT receptors. Several groups investigated a possible association of both polymorphisms with schizophrenia using casecontrol designs. [13][14][15][16][17] With the exception of Malhotra and colleagues 14 who demonstrated an association of intensity of hallucinations in neuroleptic-free schizophrenic patients with the 5-HTTLPR l/l genotype, all other studies failed to detect association with schizophrenia.In the present study we investigated linkage and association of both 5-HT transporter polymorphisms with schizophrenia in a large sample of families multiply affected with schizophrenia applying the transmission disequilibrium test (TDT).One hundred and thirty-three trios (offspring + parents) were obtained from 61 multiplex families and genotyped for both polymorphisms (Table 1). Out of 264 possible allele transmissions (for each marker one offspring escaped genotyping), 133 transmissions of VNTR-17 and 105 transmissions of 5-HTTLPR alleles were from heterozygous parents and therefore informative for TDT analysis.The contingency table (Table 2) shows that allele 10, which represents ten repeats of VNTR-17 element, was transmitted 43 times (...

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“…For these reasons genes of the serotonin system have been considered good candidates for BP (Peroutka 1995) and, thus, have been investigated in several studies. To date, results from these studies are conflicting, but overall seem to exclude the direct involvement of the 5HT receptor genes 5HT2A (Mahieu et al 1997;Zhang et al 1997;Vincent et al 1999), 5HT2C (Gutierrez et al 1996;Oruc et al 1997), and of the serotonin transporter protein gene (SLC6A4) (Kelsoe et al 1996;Oruc et al 1997;Mendez de Oliveira et al 1998;Esterling et al 1998;Vincent et al 1999;Mundo et al 2000a) in the pathogenesis of BP. However, a recent meta-analysis study of two 5HTT gene polymorphisms in BP and Unipolar Disorder (UP) on more than 1400 individuals of European Caucasian origin showed a mild association of the short allele of the promoter region polymorphism of the SLC6A4 and both BP and UP (Furlong et al 1998).…”

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confidence: 99%